9bee
alphaB-crystallin N-terminal IXI variant in a fibril state
Structural highlights
DiseaseCRYAB_HUMAN Posterior polar cataract;Alpha-crystallinopathy;Zonular cataract;Familial isolated dilated cardiomyopathy;Fatal infantile hypertonic myofibrillar myopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionCRYAB_HUMAN May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions. Publication Abstract from PubMedalphaB-crystallin is an archetypical member of the small heat shock proteins (sHSPs) vital for cellular proteostasis and mitigating protein misfolding diseases. Gaining insights into the principles defining their molecular organization and chaperone function have been hindered by intrinsic dynamic properties and limited high-resolution structural analysis. To disentangle the mechanistic underpinnings of these dynamical properties, we ablate a conserved IXI-motif located within the N-terminal (NT) domain of human alphaB-crystallin implicated in subunit exchange dynamics and client sequestration. This results in a profound structural transformation, from highly polydispersed caged-like native assemblies into an elongated fibril state amenable to high-resolution cryo-EM analysis. The reversible nature of this variant facilitates interrogation of functional effects due to perturbation of the NT-IXI motif in both the native-like oligomer and fibril states. Together, our investigations unveil several features thought to be key mechanistic attributes to sHSPs and point to a critical significance of the NT-IXI motif in alphaB-crystallin assembly, polydispersity, and chaperone activity. Dynamic fibrillar assembly of alphaB-crystallin induced by perturbation of the conserved NT-IXI motif resolved by cryo-EM.,McFarland R, Noroozi R, Miller AP, Reichow SL Nat Commun. 2024 Nov 28;15(1):10336. doi: 10.1038/s41467-024-54647-7. PMID:39609421[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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